Ethylene glycol is commonly available as automobile radiator antifreeze. Because of its sweet taste, improperly stored antifreeze is a common source of ethylene glycol poisoning, particularly in children. Ethylene glycol is rapidly absorbed from the gastrointestinal tract. Toxicity can be divided into three stages:    Stage 1—Neurological (0.5-12 hours post-ingestion)    Stage 2—Cardiopulmonary (12-24 hours post-ingestion)    Stage 3—Renal (24-72 hours post-ingestion)
4-Methylpyrazole, marketed as Antizol® (fomepizole) by Orphan Medical, Inc. is a specific antidote for the treatment of ethylene glycol poisoning. It works by inhibiting the enzyme alcohol dehydrogenase which is responsible for the conversion of ethylene glycol, which itself is relatively non-toxic, into its toxic metabolites that in turn cause the renal injury and metabolic acidosis. Antizol® is currently approved by the FDA as an antidote for ethylene glycol poisoning or suspected ethylene glycol poisoning and is recommended by poison control centers as first line therapy. See Antizol® (fomepizole) Injection, Product Monograph, Orphan Medical, Inc., 2001, the entire contents of which are hereby incorporated by reference.
Methanol is commonly available in the home in automobile windshield washer fluid and as a gas line anti-icing additive. Methanol has a minor degree of direct toxicity. Its major toxicity follows its metabolism to formic acid. Antizol® is also a specific antidote for the treatment of methanol toxicity. It works by inhibiting the enzyme alcohol dehydrogenase which is responsible for the conversion of methanol into its toxic metabolites, formaldehyde and formic acid. Again, Antizol® is approved by the FDA for use in treating methanol poisoning or suspected methanol poisoning and is recommended by poison control centers as first line therapy.
Known methods of preparing 4-methylpyrazole include the reaction of alpha, beta-unsaturated carbonyl compounds or diketones with hydrazine or hydrazine derivatives or the dehydrogenation of the corresponding 2-pyrazoline. See U.S. Pat. Nos. 3,200,128, 4,996,327, and 5,569,769. Other processes for preparing 4-methylpyrazole are disclosed in U.S. Pat. Nos. 6,229,022, 5,569,769, and 4,996,327.
4-methylpyrazole prepared by synthetic routes employed heretofore may contain impurities and toxic by-products, including pyrazole, hydrazine, and nitrobenzaldehyde. Pyrazole, like 4-methylpyrazole, is also an inhibitor of alcohol dehydrogenase, but is more toxic than 4-methylpyrazole. Pyrazole is a known teratogen (Eisses, 1995) with 10 fold less potency against alcohol dehydrogenase (T. Li et al., Acta Chem. Scan. 1969, 23, 892-902). In addition, Ewen MacDonald published a paper in 1976 that showed pyrazole in contrast to 4-methylpyrazole has a detrimental effect on brain levels of noradrenaline (E. MacDonald, Acta Pharmacol. et Toxicol. 1976, 39, 513-524). Hydrazine and nitrobenzaldehyde are known mutagens and carcinogens (H. Kohno et al., Cancer Sci. 2005, 96, 69-76).
These impurities and toxic by-products have been tolerated heretofore because methods of making ultrapure 4-methylpyrazole have not been available. The FDA has previously approved up to 0.5% pyrazole in Antizol®, but recently is requesting a higher level of purity of less than 0.1% pyrazole to qualify such high levels with animal and other studies. Therefore, while the purity of Antizol® is sufficiently high for its antidotal use in emergency medicine, such toxic impurities are not ideal. For example a pregnant woman who needs antidote therapy would risk exposure of a fetus to potentially toxic pyrazole of known teratogenicity and potentially high levels of known carcinogens. Therefore, a need exists for a 4-methylpyrzaole with even lower amounts of pyrazole and other impurities and for a synthesis of such an ultrapure 4-methylpyrazole.